Difficulty: Intermediate | Prerequisites: Organic Chemistry I (functional groups, bonding, basic reaction mechanisms, nucleophiles and electrophiles)
This set of notes covers hydrogen substitution at the carbonyl carbon, the distinction between reversible and irreversible nucleophilic additions, and the first classes of nucleophiles (carbon, hydrogen). It sits squarely in the carbonyl chemistry unit of a second-semester organic course. You should already be comfortable with arrow-pushing, the concept of a nucleophile attacking an electrophilic carbon, and the basics of oxidation states in organic molecules. If terms like "Grignard reagent" or "cyanohydrin" are new, these notes will introduce them, but you will get more from them if you have seen carbonyl groups (aldehydes, ketones) before.
Nucleophiles attack the electrophilic carbonyl carbon of aldehydes and ketones. Some of these additions are reversible (the product can revert to starting materials under the right conditions), while others are irreversible (the product is thermodynamically stable and does not go back). Knowing which category a reaction falls into tells you how to drive it to completion and what conditions to use.
Nucleophilic addition
A reaction in which a nucleophile donates an electron pair to the electrophilic carbon of a carbonyl (C=O), breaking the pi bond and forming a new sigma bond. Think of it as the nucleophile "pushing in" on the carbon while the oxygen takes the electrons.
Carbonyl group (C=O)
The functional group consisting of a carbon double-bonded to an oxygen. The carbon is electrophilic (electron-poor) because oxygen is more electronegative. In simple terms, this is the reactive site that nucleophiles target.
Reversible reaction
A reaction where the products can re-form the starting materials under the reaction conditions. The equilibrium can be shifted by changing concentration, temperature, or removing product. Think of it as a reaction that can "undo" itself.
Irreversible reaction
A reaction that proceeds to completion because the products are much more stable than the starting materials. Once the nucleophile adds, it stays. In simple terms, there is no going back.
Cyanohydrin
The product formed when cyanide ion (CN⁻) adds to a carbonyl. The resulting molecule has both a hydroxyl group (–OH) and a nitrile group (–CN) on the same carbon. Think of it as the carbonyl now carrying both an OH and a CN.
Grignard reagent (RMgX)
An organomagnesium halide (e.g. CH₃MgBr) that acts as a powerful carbon nucleophile, delivering a carbanion (R⁻) to the carbonyl carbon. In simple terms, it is a way of adding a carbon chain to a carbonyl.
PCC (pyridinium chlorochromate)
A mild oxidising agent that converts primary alcohols to aldehydes without over-oxidising to carboxylic acids. Think of it as a "gentle" oxidant for alcohols.
Jones reagent (CrO₃ / H₂SO₄)
A stronger oxidising agent that takes primary alcohols all the way to carboxylic acids and secondary alcohols to ketones.
Wittig reaction
A reaction between a phosphorus ylide (Ph₃P=CHR) and a carbonyl to replace the C=O with a C=C (alkene). In simple terms, it swaps the oxygen for a carbon, turning a ketone or aldehyde into an alkene.
Hydride donor
A reagent that delivers H⁻ (a hydrogen with a pair of electrons) to the carbonyl carbon. NaBH₄ and borane (BH₃) are common examples. Think of it as handing the carbonyl a hydrogen with extra electrons attached.
Alcohol oxidation as a route to carbonyls
Primary alcohols (R–CH₂OH) can be oxidised to aldehydes or carboxylic acids depending on the reagent:
PCC or Swern oxidation stops at the aldehyde stage (one "level" of oxidation, a 2-electron process)
Jones reagent (CrO₃/H₂SO₄) pushes the oxidation all the way to the carboxylic acid
Secondary alcohols (R₂CHOH) oxidise to ketones with either PCC or Jones reagent. There is no further oxidation possible without breaking C–C bonds.
These reactions set up the carbonyl electrophile that the rest of the lecture's nucleophiles will attack.
The Wittig reaction: turning a carbonyl into an alkene
A phosphorus ylide (Ph₃P=CHR, generated from a phosphonium salt with a strong base like BuLi) reacts with the carbonyl of an aldehyde or ketone.
The mechanism proceeds through a four-membered ring intermediate (oxaphosphetane), which collapses to give the alkene (C=C) and triphenylphosphine oxide (O=PPh₃) as a byproduct.
Net result: the C=O bond is replaced by a C=C bond. This is one of the most reliable ways to place a double bond at a specific position.
The ylide is formed from a primary or secondary alkyl halide reacting with PPh₃, followed by deprotonation.
Why this matters for the lecture
The oxidation reactions create the aldehydes and ketones that serve as substrates. The Wittig reaction is a carbon nucleophile attacking a carbonyl, and it foreshadows the pattern you will see with Grignard reagents and cyanide: a nucleophile adds to the electrophilic carbonyl carbon.
Cyanohydrin formation (HCN addition to carbonyls)
Cyanide ion (CN⁻) is the nucleophile. It attacks the electrophilic carbonyl carbon, and the oxygen picks up a proton to give the cyanohydrin product.
This reaction is reversible. The cyanohydrin can lose HCN and regenerate the carbonyl under basic conditions.
A catalytic amount of base (e.g. KCN) is used to generate the reactive CN⁻ from HCN (pKa ~9). You do not want to handle pure HCN freely, so the base liberates CN⁻ in situ.
The equilibrium favours the cyanohydrin for aldehydes and less-hindered ketones. Bulky ketones shift the equilibrium back toward starting materials because of steric strain in the product.
Amino alcohol and adrenaline connection
The lecture notes reference the formation of an amino alcohol from a carbonyl, which connects to the biosynthesis of adrenaline (epinephrine).
In biological systems, reversible carbonyl additions are common: enzymes control the equilibrium by removing or supplying products.
Hydration of aldehydes and ketones (oxygen nucleophile, preview)
Water can add across the carbonyl to give a geminal diol (hydrate). This is also reversible.
Aldehydes hydrate more readily than ketones because they are less sterically hindered and their carbonyl is more electrophilic (only one alkyl group donating electrons, versus two in a ketone).
Catalysed by either acid (protonates the carbonyl oxygen first, making the carbon more electrophilic) or base (generates hydroxide, a better nucleophile than water).
Key point for reversible reactions
If a nucleophilic addition to a carbonyl is reversible, you can manipulate the equilibrium: remove the product (Le Chatelier's principle), use excess nucleophile, or change conditions. The product is not locked in.
Grignard reagent addition (RMgX)
The Grignard reagent (e.g. CH₃MgBr) acts as a source of R⁻, a powerful carbon nucleophile.
It attacks the carbonyl carbon of an aldehyde or ketone. After aqueous workup (addition of water or dilute acid), the alkoxide intermediate is protonated to give an alcohol.
The reaction is irreversible. The C–C bond formed is strong and thermodynamically stable, so there is no tendency for it to break and revert to starting materials.
Why Grignard additions are irreversible
The driving force is the formation of a strong C–C sigma bond (bond energy ~350 kJ/mol).
The alkoxide product is a poor leaving group. For the reverse reaction to occur, the carbon would need to leave as a carbanion, which is extremely unfavourable.
Contrast this with cyanohydrin formation, where CN⁻ is a reasonable leaving group under basic conditions and the product can revert.
Practical consequence
You do not need to worry about equilibrium manipulation with Grignard reactions. Add the reagent, do the aqueous workup, and collect the product.
Grignard reagents are, however, extremely sensitive to water and must be run under anhydrous conditions. Any protic solvent will destroy the reagent by protonating the carbanion before it can attack the carbonyl.
Cyanohydrin chemistry is used industrially in the synthesis of certain amino acids (e.g. the Strecker synthesis) and in the manufacture of acrylic plastics via acetone cyanohydrin. Grignard reactions are a workhorse of pharmaceutical synthesis: building complex carbon skeletons one C–C bond at a time is how many drug molecules are assembled. The Wittig reaction is used to install specific alkene geometries in the synthesis of vitamins (notably vitamin A) and prostaglandins.
Students often think "reversible" means the reaction is slow or inefficient. It does not. A reversible reaction can be fast and high-yielding, but the product can also revert to starting materials if conditions change.
Students sometimes assume all nucleophilic additions to carbonyls are irreversible because a new bond forms. Many are reversible, and you need to know which ones.
PCC and Jones reagent are frequently confused. PCC stops at the aldehyde for primary alcohols. Jones goes all the way to the carboxylic acid. Mixing them up on an exam costs marks.
The Wittig ylide is sometimes drawn with a full negative charge on carbon and positive on phosphorus. This resonance contributor exists, but the reaction proceeds through the ylide form (P=C) attacking the carbonyl, not through a free carbanion.
⚠️ You will almost certainly be asked to classify a given nucleophilic addition as reversible or irreversible, and to explain why.
⚠️ Expect a question asking you to choose the correct oxidising agent (PCC vs Jones) for a target product. Know which one stops at the aldehyde.
⚠️ Grignard reagent questions often test whether you remember the anhydrous requirement. If water is present, the reaction fails.
⚠️ The Wittig reaction may appear as a retrosynthesis problem: given a target alkene, identify the carbonyl and ylide starting materials.
⚠️ Cyanohydrin equilibria can be tested by asking what happens when you change conditions (add base, remove product, change solvent).
True or False: PCC will oxidise a primary alcohol to a carboxylic acid.
True or False: Cyanohydrin formation is an irreversible reaction.
Fill in the blank: A Grignard reagent must be used under _______ conditions because it reacts with water.
True or False: The Wittig reaction replaces a C=O bond with a C=C bond.
Fill in the blank: In reversible nucleophilic addition, you can drive the reaction forward by applying _______ principle.
Answers: 1. False (PCC stops at the aldehyde). 2. False (it is reversible). 3. Anhydrous. 4. True. 5. Le Chatelier's.
Q: What is the product when CH₃MgBr reacts with benzaldehyde (PhCHO), followed by aqueous workup?
A: 1-Phenylethanol (a secondary alcohol). The methyl group from the Grignard adds to the aldehyde carbon, and the aqueous workup protonates the resulting alkoxide.
Q: Why is cyanohydrin formation classified as a reversible reaction, while Grignard addition is not?
A: In cyanohydrin formation, the CN⁻ can act as a leaving group under basic conditions, regenerating the carbonyl. In Grignard addition, the resulting alkoxide is a very poor leaving group, so the C–C bond does not break. The product is thermodynamically trapped.
Q: You need to convert 1-butanol into butanal. Which oxidising agent should you use, and why?
A: PCC (or Swern oxidation). Jones reagent would over-oxidise the primary alcohol past the aldehyde to butanoic acid.
Q: Draw the retrosynthetic disconnection of 2-methylbut-2-ene using the Wittig reaction. Identify the carbonyl and ylide components.
A: Disconnect at the double bond. One fragment becomes the carbonyl (e.g. acetone, (CH₃)₂C=O) and the other becomes the ylide (e.g. Ph₃P=CHCH₃, from ethyl triphenylphosphonium salt).
Q: Explain how you would shift the equilibrium of cyanohydrin formation to favour the product.
A: Use excess HCN/KCN, remove water if formed, or lower the temperature (since the forward reaction is exothermic). Applying Le Chatelier's principle in any of these ways pushes the equilibrium toward the cyanohydrin.
This material connects directly to nucleophilic substitution (SN1/SN2) from Organic Chemistry I, because you are again thinking about nucleophiles and leaving groups, only now the electrophile is a carbonyl carbon rather than an sp3 carbon. The reversibility concept resurfaces in acetal and hemiacetal formation (coming up next in most syllabuses) and in biological chemistry where enzyme-catalysed carbonyl additions are central to metabolism.
The Wittig reaction ties back to elimination reactions (E1/E2) in the sense that both create C=C bonds, but by entirely different mechanisms.
Nucleophilic addition, carbonyl chemistry, aldehyde reactions, ketone reactions, Grignard reagent, RMgX, organomagnesium, cyanohydrin, HCN addition, PCC oxidation, pyridinium chlorochromate, Jones oxidation, chromic acid, Swern oxidation, Wittig reaction, phosphorus ylide, triphenylphosphine, reversible addition, irreversible addition, Le Chatelier, equilibrium manipulation, alcohol oxidation, C–C bond formation, retrosynthesis, hydride reduction (see Part 2), oxygen nucleophile (see Part 2)